The present invention is generally in the field of ultrasound and specifically in the areas of alteration of membrane permeability and molecule-molecule interaction by ultrasound.
Ultrasound has been used for a variety of chemical applications. For example, ultrasound has been used to make phospholipid vesicles, as described in U.S. Pat. No. 4,078,052 to Papahadjopoulos, and to orient cells in a liquid flow cell analyzer apparatus, as described in U.S. Pat. No. 4,280,623 to Legorreta. Ultrasound has been used in apparatus for cleaning objects such as jewelry in the presence of a surfactant.
Ultrasound has also been used in a number of medical applications. An early review of the clinical use of ultrasound for the treatment of soft tissue injury or pain is described by James E. Griffen in "Physiological Effects of Ultrasonic Energy as it is Used Clinically", J. Amer. Phys. Therapy Assoc. 46, 18-26 (1966). One example of a clinical application of ultrasound has been to stimulate healing of soft tissue, as described by "Stimulation of Healing of Varicose Ulcers by Ultrasound" by M. Dyson et. al. in Ultrasonics, 232-235 (Sept. 1976). Ultrasound has also been described in U.S. Pat. No. 4,309,989 to Fahim as useful in the topical application of a medication, and for enhancement of transdermal drug delivery into the circulatory system, as described in U.S. patent application Ser. No. 883,111 filed July 8, 1986 by Joseph Kost, Drora Levy and Robert S. Langer entitled "Ultrasound Enhancement of Transdermal Drug Delivery". U.S. patent application Ser. No. 633,366 filed July 23, 1984, and the divisional U.S. Ser. No. 936,000 filed Nov. 28, 1986 by Joseph Kost and Robert S. Langer entitled "Ultrasonically Modulated Polymeric Devices for Delivering Compositions" disclose a process for delivering a drug from within a polymeric matrix utilizing an external source of ultrasonic energy. The ultrasonic energy degrades the polymeric matrix to effect release of the composition incorporated into the polymeric matrix. The advantage of this process is that the rate of release from the polymeric matrix can be controlled externally when the device is implanted in vivo.
Ultrasound has also been used to affect the diffusion of electrolytes through a cellophane membrane, described by I. Lenart and D. Auslander in "The Effect of Ultrasound on Diffusion through Membranes", Ultrasonics, 216-218 (Sept. 1980), and a biological membrane, described by J. Lehmann et. al., in "Uber die Wirkung von Ultraschall-Wellen auf den Ionendurchtritt durch biologische Membranen als Beitrag zur Theorie dis Therapeutischen Wirkungs-mechanismus" 311-318. Enhanced passage of ions and small molecules through cellophane membranes and frog skin is reported in "Phonophoresis" by D. M. Skauen and G. M. Zentner in Int. J. Pharm. 20, 235-245 at 238-239 (1984).
In general, none of these processes provide a means for controlling the passage of large or complex molecules suspended or dissolved in a liquid media through a membrane. Further, none of these processes alter the relationship of the molecule with its immediate environment, either a membrane or molecule of the same composition, for example, as in a molecular aggregate. Even those articles which discuss enhanced passage of topical compositions through the skin and treatment of soft tissue and connective tissue injury focus on the use of the ultrasound to generate heat while noting that the mechanisms by which these processes are controlled are unclear.
It is therefore an object of the present invention to provide a method for altering permeability of a membrane to molecules wherein the alteration is totally reversible and can be controlled as to the extent and rate of alteration.
It is a further object of the present invention to provide a method for selectively altering membrane permeability to molecules.
It is another object of the present invention to provide a method for dispersing molecular aggregates or physical complexes of molecules, particularly proteins in an aqueous solution.